Bottom Line:
Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory.However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known.Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.

ABSTRACTAstrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known. We found that humans with Alzheimer's disease (AD) had increased levels of the Gs-coupled adenosine receptor A2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice and increased the levels of Arc (also known as Arg3.1), an immediate-early gene that is required for long-term memory. Chemogenetic activation of astrocytic Gs-coupled signaling reduced long-term memory in mice without affecting learning. Like humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.

Mentions:
We next tested if astrocytic A2A receptors contribute to memory deficits in aging hAPP mice. We generated transgenic mice expressing hAPP with or without conditional ablation of astrocytic A2A receptors (Fig. 8a–b) and tested these mice in the Morris water maze and the open field. Specifically, we tested three groups of transgenic mice: singly transgenic control mice carrying two loxP-Adora2a alleles, doubly transgenic hAPP mice carrying human APP and one or two loxP-Adora2a alleles, and triply transgenic hAPP/A2A-cKO mice carrying human APP, two loxP-Adora2a alleles and Cre recombinase. Ablation of astrocytic A2A receptors did not affect the learning deficits of 15–17-month-old hAPP mice during hidden platform training (Fig. 8c), consistent with our observations that ablation of these receptors does not affect learning in young and aging mice without hAPP expression (Fig. 2). Notably, ablation of astrocytic A2A receptors enhanced the performance of hAPP mice in a probe trial 24 h after training (Fig. 8d). Specifically, hAPP mice bearing astrocytic A2A receptors showed a minimal preference for the target quadrant and an increased latency to reach the platform location compared with singly transgenic control mice without hAPP expression. In contrast, hAPP/A2A-cKO mice showed a significant preference for the target quadrant and a lower latency to reach the platform location. Swim speeds during the probe trial were comparable among the groups (Fig. 8e). Moreover, hAPP/A2A-KO mice showed less dishabituation in the open field than hAPP mice and singly transgenic controls (Fig. 8f), consistent with our findings in A2A-cHET and A2A-cKO mice without hAPP expression (Fig. 2c–f).

Mentions:
We next tested if astrocytic A2A receptors contribute to memory deficits in aging hAPP mice. We generated transgenic mice expressing hAPP with or without conditional ablation of astrocytic A2A receptors (Fig. 8a–b) and tested these mice in the Morris water maze and the open field. Specifically, we tested three groups of transgenic mice: singly transgenic control mice carrying two loxP-Adora2a alleles, doubly transgenic hAPP mice carrying human APP and one or two loxP-Adora2a alleles, and triply transgenic hAPP/A2A-cKO mice carrying human APP, two loxP-Adora2a alleles and Cre recombinase. Ablation of astrocytic A2A receptors did not affect the learning deficits of 15–17-month-old hAPP mice during hidden platform training (Fig. 8c), consistent with our observations that ablation of these receptors does not affect learning in young and aging mice without hAPP expression (Fig. 2). Notably, ablation of astrocytic A2A receptors enhanced the performance of hAPP mice in a probe trial 24 h after training (Fig. 8d). Specifically, hAPP mice bearing astrocytic A2A receptors showed a minimal preference for the target quadrant and an increased latency to reach the platform location compared with singly transgenic control mice without hAPP expression. In contrast, hAPP/A2A-cKO mice showed a significant preference for the target quadrant and a lower latency to reach the platform location. Swim speeds during the probe trial were comparable among the groups (Fig. 8e). Moreover, hAPP/A2A-KO mice showed less dishabituation in the open field than hAPP mice and singly transgenic controls (Fig. 8f), consistent with our findings in A2A-cHET and A2A-cKO mice without hAPP expression (Fig. 2c–f).

Bottom Line:
Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory.However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known.Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.

ABSTRACTAstrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known. We found that humans with Alzheimer's disease (AD) had increased levels of the Gs-coupled adenosine receptor A2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice and increased the levels of Arc (also known as Arg3.1), an immediate-early gene that is required for long-term memory. Chemogenetic activation of astrocytic Gs-coupled signaling reduced long-term memory in mice without affecting learning. Like humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.